Post on 04-Jul-2020
Matière complexe etfrustration géométrique
Sadoc’s meetingHydrophobic compaction
and protein folding
Jacques Chomilier, Isabelle Callebaut,Jean-Paul Mornon, Alain Soyer,Mathieu Lonquety, Nicolas PrudhommeIMPMC
Question: How to go from the Sequence to the 3Dstructure? This is protein foldingParadigm of structural biology: structure gives function
Hydrophobic compaction and protein folding
Protein Structure
Secondary StructuresHélice α Brins β
Primary StructureSequence
.LAVSASDLL.
TertiaryStructure
Compact
Prediction=problem of molecular conformationof amino acids
Energetic solution unrealistic (around 150amino acids)
Hydrophobic compaction and protein folding
Protein foldingGlobular Protein = Micelle(inside hydrophobic, outsidehydrophilic)
Compact (hydrogen bonds):necessity to curve thepolypeptide chain
Discrete space: (2,1,0) lattice:Sadoc’s object?
Truc from Jean-François
Hydrophobic compaction and protein folding
Folding Simulation
3.8 Å
τ1.7 Å
24 first neighbours
7 τ values from 64°to 143°
Amino acid displacements simulated by Monte Carlo
Hydrophobic compaction and protein folding
Folding Simulation
Energy = Potential of Mean Force to describeinteractions of amino acid pairs
Simulation stopped at first stages of folding : 106 MC steps
Some segments compact (proto fragments); other not(linkers)
100 simulations (different initial conditions)
Fragment limits (in amino acids) are robust: search tolook if amino acids are always surrounded by others
Hydrophobic compaction and protein folding
Proto Fragments
Mean First Neighbours during simulationMIR = Most Interacting Residues (Maxima): in thecore of the protein
Hydrophobic compaction and protein folding
MIR
Hydrophobic compaction and protein folding
MIR & nucleus92% MIR = Hydrophobic AA
Highly conserved (compulsary for folding, not forfunction)= topohydrophobic
65 % MIR: topohydrophobic ±3AA
Multiple Alignement: 90% are TH
Folding Nucleus= set of AA(hydrophobic) distributed overthe sequence, necessary toproduce the folding: hydrophobicglue
Hydrophobic compaction and protein folding
MIR & nucleus
Half the MIR correspond to nucleusMultiple structures to overcome thedegeneracy
Voronoï tesselation
Voronoï cell foreach amino acid
Hydrophobic compaction and protein folding
Hydrophobic compaction and protein folding
Voronoï tesselationNumber of Voronoïcells sharing a facewith another one(first neighbours in3D space)
Sequence separation between the two amino acids
28 Amino acids
Hydrophobic compaction and protein folding
TEFModular conception of proteins (elementaryfolding units)
TEF = Tightened End FragmentsMean = 28 Amino Acids
Super SSR
Compacity achieved by lattice simulation: Compactfragments correspond to Secondary Structures
Predict amino acids necessary for the fold (MIR)
These positions can be used as distance constraints forthe molecular modeling of domains
Among a large set of predicted structures, compacity isa very good criterium of selection (driving motor forprotein folding = hydrophobic core)
Hydrophobic compaction and protein folding
Conclusions
All developments available on a server
Hydrophobic compaction and protein folding
RPBS
Many thanks to Jean-François for:Being patient with dummiesReducing anxiousness of his colleagues
Last but not least: I am the only one whosaw him doing experiments!
Do not forget Guggenheim museum atBilbao, sculptures from Serra
Hydrophobic compaction and protein folding
Rock around Sadoc